Treatment of inflammatory bowel disease
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Treatment of inflammatory bowel disease . Goals of treatment. Goals of Treatment. Asacol ®. AZO-COMPOUNDS. Stomach. Small Intestine. Large Intestine. Mesalamine w/ eudragit-S. Azo bond. Oral 5-ASA Release Sites. Pentasa ® . Mesalamine in microgranules. Aminosalicylate.

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Treatment of inflammatory bowel disease

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Treatment of inflammatory bowel disease

Treatment of inflammatory bowel disease


Goals of treatment

Goals of treatment


Goals of treatment1

Goals of Treatment


Oral 5 asa release sites

Asacol®

AZO-COMPOUNDS

Stomach

Small Intestine

Large Intestine

Mesalamine

w/ eudragit-S

Azo bond

Oral 5-ASA Release Sites

Pentasa®

Mesalamine in microgranules


Aminosalicylate

Aminosalicylate

  • Well established role in induction and maintaining remission in UC

  • Dose –related effect in UC

  • Long term safety established

  • Efficacy in crohn’s disease is controversial due to absence of rigorous evidence and preponderance of negative studies


Steroids

Steroids


Steroids1

Steroids


Definitions

Definitions

  • Corticosteroid refractory disease

    • Patients who have active disease despite prednisolone up to 0.75 mg/kg/day over a period of four weeks.

  • Corticosteroid dependent disease; Patients who are either

    • (a) unable to reduce corticosteroids below the equivalent of prednisolone 10 mg/day (or budesonide below 3 mg/day) within three months of starting corticosteroids, without recurrent active disease, or

    • (b) who have a relapse within three months of stopping corticosteroids.

The aim should be to withdraw corticosteroids completely.

E F Stange, S P L Travis; ECCO Consensus on the diag&Mang of CD”Gut 2006;55(Suppl I.)


Steroids2

Steroids

  • Crohn’s disease: 50% of patients will require treatment with steroids.

  • Of those 28% will become steroid dependent

  • Ulcerative colitis: 34% of patients will require treatment with steroids.

  • Of those 22% will become steroid dependent


Steroid

Steroid

  • Effective for the short-term control of symptoms of Crohn's disease but are neither effective nor safe for long-term maintenance of response.

  • In patients with disease that is refractory to or dependent on glucocorticoids, steroid-sparing strategies should be considered, including immune modulators or surgery.


Principles of steroid use in ibd

Principles of steroid use in IBD


Steroid adverse effects

Steroid adverse effects


Immunomodulators azathioprine and 6 mercaptopurine

Immunomodulators: azathioprine and 6 -mercaptopurine


Indications of immunosuppressant

Indications of immunosuppressant


Safety and tolerability

Safety and tolerability

  • Flu like symptoms occuring after 2-3 weeks and resolve on discontinuation of RX (20%)

  • Hepatotoxicity and pancreatitis(<5%)

  • Leukopenia(<3%)

  • Good long term tolerance

  • Can be given during pregnancy

  • ? ↑ risk of neoplasm


Methotrexate

Methotrexate


Cyclosporine

Cyclosporine

  • Competetively binds to and inhibit calmodulin dependent calcineurin, leading to suppression of T-cell and IG E receptor signaling pathways.

  • IV Cyclosporine has a rapid onset of action

  • Neither intravenous nor oral low-dose cyclosporine has proven efficacy in patients with luminal CD.

  • High toxicity limiting its use


Biologic treatment

Biologic treatment


Treatment

Treatment


Treatment of ulcerative colitis

Treatment of ulcerative colitis


Disease location

Disease location


Topical treatment

Topical treatment


Advantage of topical therapy

Advantage of topical therapy


Mild to moderate distal colitis induction of remission

Mild to moderate distal colitis: induction of remission

  • Topical 5 –ASA is more effective than topical steroid and oral 5-ASA

  • Combination of oral and topical 5-ASA is more effective than either alone

  • Patient unresponsive to topical therapy: po steroids


Mild to moderate distal colitis maintenance of remission

Mild to moderate distal colitis: maintenance of remission

  • Topical and oral 5-ASA :Effective in maintainaing remission

  • Combination of oral and topical 5-ASA is more effective than oral 5-ASA alone

  • Topical and oral steroid: no role


Mild to moderate extensive colitis induction of remission

Mild to moderate extensive colitis: induction of remission

  • Oral 5-ASA is the first line of therapy

  • Oral steroids are reserved for: - refractory patients to PO +/- topical 5-ASA - troubling sxs requiring rapid improvement


Mild to moderate extensive colitis maintenance of remission

Mild to moderate extensive colitis: maintenance of remission

  • All 5 –ASA are effective in preventing relapse

  • Azathioprine or 6-MP may be used: -steroid sparing agent in steroid dependent patients -steroid refractory patients who are not acutely ill -remission not adequately maintained on 5-ASA


Management of severe colitis

Management of severe colitis

  • Patients with severe colitis refractory to maximal oral prednisone, oral 5-ASA and topical RX, or presents with toxicity should be hospitalized for IV steroids

  • Patients not responding within 7-10 days of maximal medical therapy should be offered alternative treatment: -biologic treatment -cyclosporin- surgery


Cyclosporine1

Cyclosporine

  • Cyclosporine has a rapid onset of action (more rapid than AZA, 6-MP, or methotrexate) and when administered intravenously has been shown to be effective in the management of patients with severe UC.

  • It often demonstrates clinical efficacy within 1 week when administered intravenously.

  • Oral cyclosporine has a possible role in the induction of a clinical response in UC and short term in the maintenance of an intravenous cyclosporine-induced response, allowing time for the slow-acting purine analogues to become effective.


Biologic treatment1

Biologic treatment

  • Infliximab is the only FDA approved treatment for patients with moderate-severe ulcerative colitis

  • ACT 1 study: treatment with infliximab can prevent hospitalizations and surgery for UC patients in the first year of treatment


Treatment of inflammatory bowel disease

Ulcerative Colitis: Mild to Moderate

Acute flare

Exclude entericpathogen

Extensive

Left side

Oral 5-ASA

Patient willing totake rectal therapy

Patient unwilling to take rectal therapy

Consider rectal therapy(5-ASA and/or steroid)

Maintain

Maintainoral 5-ASA

Oral steroid

Responseadequate

Responseinadequate

Response adequate

Considerincreased dose

Response

inadequate

Oral 5-ASA

Responseinadequate

Responseadequate

Response

inadequate


Treatment of inflammatory bowel disease

Ulcerative Colitis: Moderate to Severe

Moderate

Severe

Infliximab

IV Steroid

ConsiderCyA

Oral steroid

6MP/AZA

Taper

Success

Colectomy

Successful

Maintain on5-ASA and observe

Maintaininfliximab

Maintain6-MP/AZA

Inadequate response

Inadequate response

Adequate response

Response

Unsuccessful

No

response

Failure

No

response

Response


Treatment of inflammatory bowel disease

Therapeutic Pyramid for

Active UC

Severe

Surgery

Cyclosporine

Infliximab

Moderate

Systemic Corticosteroids

AZA/6-MP

Oral Steroids

Mild

Aminosalicylates


Indication for surgery

Indication for surgery

  • Total colectomy with ileoanal pouch anastomosis is the procedure of choice for patients with UC:


Indications for surgery in uc

Indications for surgery in UC

Analysis of 917 UC patients at Heidelberg University between 1982 and 2001

Perforation

6%

Toxic uc

10%

Colorectal ca 7%

Dysplasia 3%

Failure of

medical therapy

74%

Hoffmann et al. Chronisch-Entzündliche Darmerkrankungen. Thieme 2004


Potential complications of uc surgery

Potential Complications of UC Surgery

  • 3-10 stools/24 hrs 1

  • Decrease in female fertility (38-54%)3-5

  • Pouchitis (10-60%)1

  • Small bowel obstruction (20%)1

  • Abscesses & fistulae (5-12%)6

  • Pouch-vaginal fistula (4%)1

  • Long-term continence problems (15%)6

  • Impotence (1.5%)2

1Sagar PM, Pemberton JH. In Satsangi J, Sutherland L, et al, eds. Inflammatory Bowel Diseases. Spain: Elsevier Limited; 2003:491 511.

2Pemberton JH, et al. Ann. Surg. 1987;206(4):504-513. 3Olsen, KO, et al. Gastroenterology. 2002;122:15-19.

4Johnson P, et al. Dis Colon Rectum. 2004;47;1119–1126. 5Gorgun E, et al. Surgery. 2004;136(4):795–803.

6Stange et al. Colitis ulcerosa – Morbus Crohn.Uni-Med Verlag AG 1999.


Pouchitis

Pouchitis

  • Idiopathic inflammation of “pouch” after ileoanal pouch anastomosis


Treatment of crohn s disease

Treatment of crohn’s disease


Mild to moderate luminal active disease

Mild to moderate luminal active disease

  • Despite the use of oral mesalamine treatment in the past, new evidence suggests that this approach is minimally effective as compared with placebo and less effective than budesonideor conventional corticosteroids


5 asa in crohn s disease

5-ASA in crohn’s disease

  • No mesalamine product has been FDA approved for either induction or maintenance of remission

  • Not effective in maintaining post-operative remission.


Mild to moderate luminal active disease1

Mild to moderate luminal active disease

  • Oral budesonide is more effective than placebo, or 5-ASA and have similar efficacy to conventional po steroids for the treatment of mild-moderate active CD involving distal ileum and/or right colon.

  • Budesonide is recommended for use as primary therapy for patients with mild to moderate active CD localized to ileum and/or right colon


Moderate to severe luminal disease

Moderate to severe luminal disease

  • Prednisone (40 -60 mg/day) until resolution of symptoms

  • Infection or abscess requires antibiotic therapy or drainage

  • Azathioprine and 6-MP are effective in maintaining a steroid-induced remission

  • Parenteralmethotrexate (25 mg/week) :effective for steroid-dependent and steroid-refractory CD


Biologic treatment2

Biologic treatment

  • Anti TNF monoclonal Ab : infliximab, adalimunab and cetrolizumab are effective for: -moderate- severely active CD not responding despite complete and adequate therapy with a steroids or immunosuppressive agent -as alternative to steroid therapy in selected patients in whom steroid is contraindicated

  • The anti-alpha 4 integrinAb : natalizumab, is effective for patients with moderate to severely active disease who had an inadequate response to anti TNF AB or unable to tolerate it


Therapeutic strategies step up

Therapeutic Strategies:Step up

Sequential escalation based upon symptoms, usually starting with the

efficacysafest medication but with the least

Most prevalent strategy

Advantages: minimize risks of adverse drugs effects

Disadvantages: risk of inadequate treatment, not targeting

the underlying process, i.e. the inflammation and the

potential complications


Therapeutic pyramid for treatment of luminal non fistulizing crohn s disease

Therapeutic pyramid for treatment of luminal non fistulizing crohn’s disease

Severe

Mild


Therapeutic strategies top down

Therapeutic Strategies:Top down

Therapy with a potent agent since the beginning

Advantages: strong suppression of inflammation

from diagnosis

Disadvantages: Expensive, treats all patients as if

they have identical risk and lead to unnecessary

exposure to adverse drug effects


Treatment of perianal fistula

Treatment of perianal fistula

  • Mesalamine:

  • No clinical trial has demonstrated any beneficial effect of mesalazine on fistula healing.

  • Steroids:

  • Not effective


Treatment of perianal fistula1

Treatment of perianal fistula

  • Antibiotics: widely used first-line treatment for fistulas in patients with Crohn’s disease

  • Dual role in the treatment of fistulas: as a primary therapy and as an adjuvant therapy for abscesses and infections caused by the fistula.

  • Metronidazole:

  • Most studied antibiotic

  • Fistulas generally respond to administration of this antibiotic after 6–8 weeks, but therapy is typically continued for 3–4 months.

  • Ciprofloxacin:

  • The beneficial effects of the fluoroquinolone antibiotic, ciprofloxacin, have demonstrated in various studies.

  • combination treatment with metronidazoleand ciprofloxacin has shown beneficial effects


Treatment of perianal fistula2

Treatment of perianal fistula

  • Immunosuppressives:

  • Azathioprine and 6-mercaptopurine: seem to be effective treatments for perianal fistulas

  • Methotrexate: Not recommended

  • Cyclosporin: Not recommended


Treatment of perianal fistula3

Treatment of perianal fistula

  • Biologic: In contrast to azathioprine and 6- MP, the clinical effects of biologics begin to be seen soon after initiation of therapy

  • Surgery:

  • The reported incidence of perianal fistulas that require surgery in patients with Crohn’s disease varies from 25–30%.

  • The goals of surgery in these patients are to cure the fistula(s) while preserving anal sphincter function.


Treatment of internal fistula

Treatment of internal fistula

  • If asymptomatic: no need for tratment

  • Symptomatic :surgical resection of diseased bowel segment


Factors predicting prognosis

Factors predicting prognosis


Indication of surgery in crohn s disease

Indication of surgery in crohn’s disease

  • Surgical resection, stricturoplasty, or drainage of abscesses is indicated to treat complications or medically refractory disease

  • Surgical resection rarely “ cures ” CD

  • Nevertheless, surgical intervention is required in up to two thirds of patients

  • The most common indications for surgical resection are refractory disease despite medical therapy or side effects of medication (steroid dependence)


Indications for surgery

Indications for surgery


Preventing post op recurrence

Preventing post-op recurrence


Stricturoplasty

Stricturoplasty

  • Stricturoplasty has been advocated as an important alternative to resection in the treatment of selected fibrotic strictures of the small bowel and should be attempted when possible to help avoid: - impaired nutrient absorption -steatorrhea -bacterial overgrowth -short bowel syndrome


Cancer in ibd

Cancer in IBD


Cancer in crohn s disease

Cancer in crohn’s disease

  • When Crohn's disease involves the large bowel, the excess risk of colorectal cancer appears to be similar to that in ulcerative colitis of similar extent.

  • The characteristics and prognosis of colorectal cancer in Crohn's disease also are similar to those for colorectal cancer in ulcerative colitis.

  • surveillance colonoscopy has been recommended as a means of early detection.


Colorectal cancer risk in ulcerative and crohn s colitis

COLORECTAL CANCER RISK IN ULCERATIVE AND CROHN’S COLITIS


Colorectal cancer in ulcerative colitis

Colorectal cancer in ulcerative colitis

  • Patients with UC have an increased risk of colorectal cancer.

  • This risk is dependent on several factors

  • the most important -duration -extent of disease

  • Other risk factors : -PSC -family history of colon cancer -age at diagnosis of disease -severity of inflammation


Risk factors for colon cancer in ulcerative colitis and crohn s colitis

Risk Factors for Colon Cancer in Ulcerative Colitis and Crohn’s colitis

Importance

Risk Factor

Choi PM, et al. Gastroenterol Clin North Am 1995;24:671-87.

Eaden J. Am J Gastroenterol 2000;95:2710-2719.


Treatment of inflammatory bowel disease

Ekbom, et al NEJM, 1990


Colorectal cancer in ulcerative colitis1

Colorectal cancer in ulcerative colitis

  • The incidence of colon cancer in UC has been estimated at approximately 7% to 10% at 20 years of disease and as high as 30% after 35 years of disease.

  • in general, the risk of CRC may be estimated to increase within the range of 0.5% to 1.0% per year after 8 to 10 years of disease in patients with extensive UC


Colorectal cancer in ulcerative colitis2

Colorectal cancer in ulcerative colitis


Protective factors

Protective factors


Future of ibd treatment

Future of IBD treatment

  • 5 ASA will be administered once daily in ulcerative colitis , and decrease in crohn’sdisaease

  • Treatment of IBD with steroids will decrease due to lack of long term efficacy and side effects

  • The use of anti-TNF therapy will most likely increase

  • They will be used earlier in the course of CD with more rigorous treatment goal: mucosal healing


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